This application addresses broad Challenge Area 15 "Translational Science" and the specific Challenge Topic 15-NS-103: "Demonstration of 'proof-of-concept'for a new therapeutic approach in a neurological disease." Frontotemporal dementia (FTD) is a devastating and progressive neurodegenerative disease characterized by profound behavioral and personality changes. FTD has been under-diagnosed and is now recognized as the most common form of dementia in people under age 65. There are no therapies for FTD, and affected individuals usually die within 5-8 years. In our aging population, FTD presents a huge burden for patients, caregivers, and the health care system. However, thanks to the recent identification of disease-causing genetic mutations, there is now new hope for major insights into FTD pathogenesis and for new therapies. Loss-offunction mutations in the human progranulin gene (GRN) account for ~20% of cases of familial FTD via a disease mechanism of GRN haploinsufficiency (loss of 50% of the protein expression);more than sixty pathogenic GRN mutations have been reported in the past two years. Many of these mutations are nonsense mutations (that generate a premature stop codon and degradation of the mutant GRN mRNA). Thus, emerging data suggest that FTD may be, at least in part, a disease of deficiency of progranulin. We hypothesize that increasing progranulin levels may provide an important therapeutic strategy for FTD patients with progranulin deficiency and possibly for all FTD patients. The goal of this study therefore is to identify and provide proof-ofconcept studies for drugs that can increase GRN expression. In this proposal, we focus on two key mechanisms to increase GRN expression: 1) increasing expression from mutant GRN alleles in those subjects with nonsense mutations, and 2) increasing expression from the normal GRN allele. Aim 1 focuses on increasing expression from GRN nonsense alleles. We will determine the efficacy of nonsense mutation- suppressing drugs to elevate progranulin levels in a murine GRN nonsense mutation model. Aim 2 focuses on increasing expression from normal GRN alleles. For this aim, we will perform high-throughput screening assays to identify FDA-approved compounds that increase normal GRN expression. We will then determine if candidate compound(s) increase endogenous Grn expression in murine models both in vitro and in vivo. For subjects with GRN haploinsufficiency, treatment simply by increasing GRN expression by as little as 10-15% may be hugely beneficial. Moreover, agents that increase GRN expression in general may be useful for all causes of FTD and even for a variety of neurodegenerative diseases. Aim 3 is to test the compounds identified as successful in Aims 1 and 2 in human cell lines derived from FTD patients with GRN haploinsufficiency. The goal will be to identify compounds that are efficacious in human FTD cell lines and to lay the groundwork for human clinical trials. Using progranulin as the focus, the studies we propose will help to rapidly identify and test new therapies for this devastating neurodegenerative disease. PUBLIC HEALTH RELEVANCE: One form of frontotemporal dementia (FTD) is frequently caused by nonsense mutations in a presumed signaling protein, Progranulin (GRN). This project aims to develop and perform preclinical testing of a combinatorial drug treatment approach that aims at restoring normal GRN levels and function, as an approach to prevent or delay FTD onset.